Process for the preparation of Caprolactam Cgrp Antagonist

ABSTRACT

An efficient syntheses for the preparation of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.

International patent applications PCT/US2004/010851, filed Apr. 9, 2004(published as WO2004/092166 on Oct. 28, 2004) and PCT/US2004/011280,filed Apr. 9, 2004 (published as WO2004/092168 on, Oct. 29, 2004), andU.S. application Ser. No. 10/838,835 (issued as U.S. Pat. No. 6,953,790on Oct. 11, 2005) disclose compounds useful for the treatment ofdiseases or conditions of humans or other species which can be treatedwith inhibitors, modulators or promoters of the Calcitonin Gene-RelatedPeptide (CGRP) receptor function. Such diseases or conditions includethose mentioned in the referenced applications, and specifically includemigraine and cluster headache.

BACKGROUND OF THE INVENTION

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1:

is a potent CGRP modulator. The laboratory preparation of compound 1 isdescribed in international patent applications PCT/US2004/010851 andPCT/US2004/011280, and in U.S. patent application Ser. No. 10/838,835.

The laboratory preparation of certain intermediates employed in thesynthesis of compound 1 is likewise described in the above-listedapplications. Such intermediates include the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2:

and the intermediate2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, 3:

and salts thereof, including2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride:

Prior techniques for synthesizing compound 1, including syntheses ofintermediates 2 and 3, are relatively inefficient and costly from thestandpoint of production and/or may result in sub-optimal salt and/orsolvate forms for further synthesis and/or development.

With respect to intermediate 2, it has been found that prior techniquesof synthesis require an inordinate number of steps, including a largenumber of isolation steps, making the overall synthetic process slow aswell as costly. Thus there remains a need for an improved syntheticroute to compound 1 wherein the synthetic route to compound 2 isefficient and economical.

Prior techniques for making intermediate 3 are likewise costly andinefficient. Such known routes start with a reductive alkylation of2,3-diaminopyridine (“DAP”) followed by CDI-mediated cyclic ureaformation and, lastly, acidic Boc-group deprotection/salt formation.This “DAP” route is characterized by high-cost starting materials andreagents as well as a low yielding first step, resulting in prohibitiveoverall costs. Thus, there remains a need for an improved syntheticroute to compound 1 wherein the synthetic route to intermediate 3 isefficient and economical.

Finally, prior techniques for making compound 1, which techniques employ4-nitrophenyl chloroformate as the carbonyl source, result in less thanoptimal yields. Such prior techniques further require that the neutralform of compound 1 be isolated prior to conversion to preferred saltforms. Moreover, previous laboratory-made forms of compound 1, includingfree base forms and salt forms, possessed less than ideal propertieswith respect to stability and bioavailability. Thus, there remains aneed for an improved synthetic route to compound 1, and pharmaceuticallyacceptable salts thereof, which is amenable to large scale productionformulation, storage and distribution.

SUMMARY OF THE INVENTION

The present invention provides an efficient synthesis for thepreparation ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, by coupling the intermediates(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, particularly the hydrochloride form thereof; and2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, 3,particularly the dihydrochloride form, with 1,1′-carbonyldiimidazole ascarbonyl source. The present invention further provides an efficientpreparation of potassium salt forms ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1 including the potassium ethanolate form.

Additionally, the present invention provides an efficient syntheses forthe preparation of intermediates(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, particularly the hydrochloride form; and2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, 3,particularly the dihydrochloride form.

The invention additionally resides in the superior properties of thepotassium salt ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, including the potassium salt ethanolate and potassium salt hydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, and its potassium salt ethanoate:

The syntheses ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, and its potassium salt ethanoate, is depicted in Scheme 1:

Scheme 1A depicts an efficient method of synthesizing the neutral formof compound 1 from intermediates 2 and 3 using 1,1′-carbonyldiimidazoleas the carbonyl source; Scheme 1B depicts an efficient method ofsynthesizing a potassium salt form of compound 1 starting from theneutral form of compound 1; and Scheme 1C depicts the efficientsynthesis of a potassium salt form of compound 1 directly fromintermediates 2 and 3 using 1,1′-carbonyldiimidazole as the carbonylsource, without isolation of the neutral form of compound 1.

Thus, in one embodiment of the invention provides a process for thepreparation ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, comprising reacting(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride and2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride in the presence of 1,1′-carbonyldiimidazole.

Another embodiment of the invention provides a process for thepreparation of the potassium salt ethanolate form ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, comprising the steps of:

-   -   (1) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        hydrochloride and        2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine        dihydrochloride in the presence of 1,1′-carbonyldiimidazole;    -   (2) isolating        N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,        1; and    -   (3) reacting said        N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin        1-yl)piperidine-1-carboxamide, 1, with potassium tert-butoxide        and ethanol.

Yet another embodiment of the invention provides a process for thepreparation of the potassium salt ethanolate form ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,1, without the necessity to isolate the neutral form of compound 1,comprising the steps of:

-   -   (1) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        hydrochloride and        2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine        dihydrochloride in the presence of 1,1′-carbonyldiimidazole; and    -   (2) reacting of        N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin        1-yl)piperidine-1-carboxamide, 1, with potassium tert-butoxide        and ethanol.

As described in the reaction schemes and Examples contained herein, thepotassium salt ethanolate form ofN-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamideis obtained under anhydrous conditions. When the described reaction isperformed in the presence of water, the reaction produces either pureethanolate, pure hydrate or a mixed ethanolate/hydrate, depending onwater content. The isolated potassium salt ethanolate or mixedethanolate/hydrate converts to the hydrate over time due to the presenceof water in the air.

Another aspect the invention provides a process for the preparation ofthe intermediate(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2:

and salts thereof, in particular its hydrochloride salt:

The syntheses of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2 and its hydrochloride salt is depicted in Scheme 2:

Scheme 2 depicts the direct formation of the chloroacetophenone fromcheap and readily available difluorobenzene; the selective formation ofthe Z-allylic alcohol using palladium catalysis; the use of acrystallization driven asymmetric transformation to set the aminestereocenter; followed by a cis-selective hydrogenation andepimerization to set the benzylic stereocenter and trans geometry.

Thus, an embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, comprising the steps of:

-   -   (1) hydrogenating a        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt, in the presence of a cis-selective catalyst, to form a        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt;    -   (2) reacting the        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt with R₃N, wherein each R is independently C₁₋₄alkyl, and a        hydroxyl nitrobenzaldehyde, to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,        2.

An additional embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, comprising the steps of:

-   -   (1) hydrogenating a        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt, in the presence of a cis-selective catalyst, to form a        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt;    -   (2) reacting the        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt with R₃N, wherein each R is independently C₁₋₄alkyl, and a        hydroxyl nitrobenzaldehyde, to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;        and    -   (3) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        with HCl.

A further embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, comprising the steps of:

-   -   (1) hydrogenating        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        di-toluoyl tartrate salt, in the presence of a cis-selective        palladium catalyst, to form        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt;    -   (2) reacting        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt with Et₃N and        2-hydroxy-5-nitrobenzaldehyde to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,        2.

A still further embodiment of the invention provides a process for thepreparation of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, comprising the steps of:

-   -   (1) hydrogenating        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        di-toluoyl tartrate salt, in the presence of a cis-selective        palladium catalyst, to form        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt;    -   (2) reacting        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt with Et₃N and        2-hydroxy-5-nitrobenzaldehyde to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;        and    -   (3) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        with HCl.

Yet another embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, comprising the steps of:

-   -   (1) reacting        3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one        with 2-hydroxy-5-nitrobenzaldehyde and a chiral acid to form an        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt;    -   (2) hydrogenating a        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt, in the presence of a cis-selective catalyst, to form a        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt;    -   (3) reacting the        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt with R₃N, wherein each R is independently C₁₋₄alkyl, and a        hydroxyl nitrobenzaldehyde, to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.

An additional embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, comprising the steps of:

-   -   (1) reacting        3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one        with 2-hydroxy-5-nitrobenzaldehyde and a chiral acid to form an        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt;    -   (2) hydrogenating a        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt, in the presence of a cis-selective catalyst, to form a        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt;    -   (3) reacting the        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        salt with R₃N, wherein each R is independently C₁₋₄alkyl, and a        hydroxyl nitrobenzaldehyde, to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;        and    -   (4) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        with HCl.

A further embodiment of the invention provides a process for thepreparation of the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,2, comprising the steps of:

-   -   (1) reacting        3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one        with 2-hydroxy-5-nitrobenzaldehyde and ditoluoyl-L-tartaric acid        to form an        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt;    -   (2) hydrogenating        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        di-toluoyl tartrate salt, in the presence of a cis-selective        palladium catalyst, to form        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt;    -   (3) reacting        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt with Et₃N and        2-hydroxy-5-nitrobenzaldehyde to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,        2.

A still further embodiment of the invention provides a process for thepreparation of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, comprising the steps of:

-   -   (1) reacting        3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one        with 2-hydroxy-5-nitrobenzaldehyde and ditoluoyl-L-tartaric acid        to form an        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        salt;    -   (2) hydrogenating        (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium        di-toluoyl tartrate salt, in the presence of a cis-selective        palladium catalyst, to form        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt;    -   (3) reacting        (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium        di-toluoyl tartrate salt with Et₃N and        2-hydroxy-5-nitrobenzaldehyde to form        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;        and    -   (4) reacting        (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one        with HCl.

It will be recognized by one skilled in the art that chiral acids otherthan L-ditoluoyl tartaric acid, may be employed. Similarly, it will berecognized that the purpose of the hydroxyl nitrobenzaldehyde is as anepimerization agent, and thus alternate compounds capable of epimerizingthe appropriate substituents on the azepinone ring may be used. It willalso be recognized by the skilled artisan that salts other than thechloride salt may be formed. Thus, in the several embodiments recitedabove wherein the final step recites the use of HCl to form a chloridesalt, other acids such as HBr, H₂SO₄ and HNO₃ and others may also formuseful salts.

In still another aspect the invention provides a process for thepreparation of the intermediate2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride, 3:

and salts thereof, including the dihydrochloride salt. The syntheses of2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, 3, and2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride, is depicted in Scheme 3:

In Scheme 3, 3-Amino-2-chloropyridine (“ACP”) is reductively alkylatedin a first step. 3-amino-2-chloropyridine is reacted with ethyl4-oxo-1-piperidinecarboxylate in the presence of IPAC, trifluoroaceticacid and sodium triacetoxyborohydride (“STAB”) to form the amine ethyl4-[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate. In a secondstep, a urea is formed in a reaction of the amine with chlorosulfonylisocyanate (CSI), typically in the presence of H₂O and THF. In a thirdstep, the urea is cyclized in the presence of a palladium catalyst.Typically, the urea is reacted in the presence of NaHCO₃, i-PrOH,Pd(OAc)₂ and bis-(diphenylphosphino)butane (dppb) to obtain the cyclicurea. In a further ethyl carbamate deprotection step the cyclic urea isreacted in the presence of NaOH and EtOH to obtain the pyridineheterocycle bis-HCl salt 3.

As described above and in the Examples which follow, this ACP routecomprises four synthetic steps and features a reductive alkylation,primary urea formation using chlorosulfonyl isocyanate, Pd-catalyzedcyclization of the primary urea and hydrolysis of the ethyl carbamate.The starting materials/reagents for the ACP route are significantly lessexpensive than those required for the DAP route and all the steps arehigh yielding.

Thus, in one aspect of the invention provides a process for thepreparation of the intermediate2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride, 3, comprising the steps of:

-   -   (1) reacting 3-amino-2-chloropyridine with C₁₋₄alkyl        4-oxo-1-piperidinecarboxylate, in the presence of        trifluoroacetic acid and sodium triacetoxyborohydride to form        C₁₋₄alkyl        4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;    -   (2) reacting the C₁₋₄alkyl        4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with        chlorosulfonyl isocyanate to form C₁₋₄alkyl        4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;    -   (3) reacting the C₁₋₄alkyl        4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate        in the presence of NaHCO3, Pd(OAc)2 and        bis-(diphenylphosphino)butane to form C₁₋₄alkyl        4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate;    -   (4) reacting the C₁₋₄alkyl        4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate        with HCl to form        2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine        dihydrochloride.

An additional embodiment of the invention provides a process for thepreparation of the intermediate2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride, 3, comprising the steps of:

-   -   (1) reacting 3-amino-2-chloropyridine with ethyl        4-oxo-1-piperidinecarboxylate, in the presence of        trifluoroacetic acid and sodium triacetoxyborohydride to form        ethyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;    -   (2) reacting the ethyl        4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with        chlorosulfonyl isocyanate to form ethyl        4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;    -   (3) reacting the ethyl        4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate        in the presence of NaHCO3, Pd(OAc)2 and        bis-(diphenylphosphino)butane to form ethyl        4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate;    -   (4) reacting the ethyl        4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate        with HCl to form        2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine        dihydrochloride.

The invention is not limited to specific embodiments described in thisapplication, and in fact includes additional features not expresslydescribed above, including but not limited to the use of particularsolvents and reaction conditions, the use of particular reagent forms(including neutral forms of intermediates 2 and 3, and salt forms otherthan HCl salt forms), and the use or no-use of particular separation orisolation techniques, and other features.

Several abbreviations, acronyms and other shorthand is presented herein.Although these terms are known to those skilled in the art, presentedbelow is a table summarizing these terms:

IPAc isopropylacetate IPA ispropanol nHexLi n-hexyl lithium THFtetrahydrofuran BOC tert-butyloxycarbonyl CDI 1,1′-carbonyldiiidazoleMTBE Methyl tert-butyl ether tol toluoyl or toluene dppebis-(diphenylphosphino)ethane dppb bis-(diphenylphosphino)butane DMAcdimethylacetamide TFA trifluoroacetic acid ACP 3-amino-2-chloropyridineSTAB sodium triacetoxyborohydride

EXAMPLE 1N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

To a 12 L 4 necked flask equipped with overhead stirrer, thermocoupleand nitrogen inlet was charged Caprolactam HCl salt 2—MTBE solvate (412g corrected as HCl salt; MTBE solvate typically 78-79 wt % HCl salt).THF was then added at room temperature (4.1 L; 10 mL/g) followed bytriethylamine (194 ml; 1.2 eq). The slurry was aged at room temperature.To a separate 22 L 4 necked flask equipped with overhead stirrer,thermocouple and nitrogen inlet was charged CDI (233 g; 1.25 eq) and THF(2.3 L; 10 ml/g relative to CDI). The solution was aged at roomtemperature. The caprolactam slurry solution was added to the CDIsolution over 1-1.5 h at room temperature then aged at room temperatureover 1 hour after which the reaction was assayed for conversion to thecaprolactam acyl imidazole intermediate (>98.5 LCAP conversion). Thepiperidine heterocycle 3 (418 g; 1.25 eq) was then added followed byEt₃N (419 mL; 2.6 eq). The slurry was heated to 60° C. and heldovernight at that temperature. HPLC assay showed 97.4 LCAP conversion.Water was then added (190 mL; ˜3 vol % relative to THF) and reactionmixture aged at 60° C. for an additional 2.5 hours after which LC assayshowed 99.8 LCAP conversion. The reaction mixture was then cooled to 15°C. then quenched with MTBE (3.1 L; 7.5 ml/g) and washed with 10% (w/w)aq citric acid soln (4×2 L; 5 ml/g). The organic layer was then assayedfor imidazole and piperidine acyl imidazole impurities (<0.2 LCAP) Theorganic layer was then washed with 5% (w/w) aq sodium bicarbonatesolution (2 L; 5 ml/g) then water (2 L; 5 ml/g) then passed through aninline filter to give 620 g assay of desired product. (95.3% assayyield, 98 LCAP purity).

EXAMPLE 2N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Caprolactam 2 (8.23 kg≡5.60 kg caprolactam HCl salt based on 68 wt %assay)) was charge to an inerted vessel A with THF (66.4 L) andtriethylamine (1.90 kg). A vessel B was charged with CDI (3.163 kg) andTHF (30 L). The contents of vessel A were transferred to vessel B over1.5 h and the mixture in vessel B aged for 1 h. At that point HPLCanalysis showed the formation of caprolactam acylimidazole to becomplete. The piperidine heterocycle 3 (5.0 kg) was charged to vessel Bfollowed by triethylamine (4.12 kg). The batch was heated to 60° C. andaged overnight when HPLC analysis showed the coupling was complete (<0.2LCAP caprolactam-CDI adduct remaining). MTBE (49 l) and 10% aqueouscitric acid (29 l) were added and the phases separated. The organicphase was washed again with 10% aqueous citric acid (29 L) and then with5% NaHCO₃ solution (2×28 L). The pH of the last aqueous phase was 9 atthat point. The organic phase was washed with DI water (27 L) and theMTBE solution was assayed for compound 1, with the assay yield ofneutral compound 1 equal to 8.49 kg, 96.0%. The HPLC assay also showedstill 1.0 LCAP of the N-acylimidazole adduct remaining. Therefore, theMTBE solution was washed again with 10% aqueous citric acid (2×29 L), 5%aqueous NaHCO₃ (2×28 L) and water (27 L). HPLC assay of the MTBEsolution was performed again. Assay yield neutral 454=8.27 kg, 93.5%,98.9 LCAP, <0.1 LCAP N-acylimidazole adduct.

EXAMPLE 3N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,Potassium Salt Ethanolate

The MTBE solution of compound 1 (8.27 kg) was charged to an inertedvessel through a 0.1 μm cartridge filter and concentrated down to 30 Lusing partial vacuum and keeping T<40° C. Ethanol (116 L) was chargedand the solution concentrated down to 30 L again under vacuum at <40° C.Ethanol (116 L) was added and the solution analyzed for residualTHF/MTBE content (none detected). Potassium tert-butoxide (1.720 kg) wascharged as a solid to the vessel and the mixture warmed up to 45° C. todissolve all solids. The batch was then concentrated down to a finalvolume of 58 L (7 ml/g based on neutral 454) at <40° C. The resultingslurry was left cooling to room temperature overnight before filtering.The filter cake was washed with cold ethanol (25 L) and the solid driedunder vacuum at 40° C. The solid was de-lumped using a co-mill.Yield=7.97 kg, 84%.

EXAMPLE 4N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5b]pyridin-1-yl)piperidine-1-carboxamide,Potassium Salt Ethanolate

A 250 mL, 3-neck round bottom flask was equipped with a mechanicalstirrer and claisen adapter with nitrogen inlet and thermocouple.Compound 1 (12.49 g) and punctilious ethanol (165 mL) were charged tothe vessel. The suspension was warmed in a 60° C. oil bath and thesuspension agitated. All the solids dissolved and a homogeneous solutionwas obtained when the internal temperature reached 38° C. Thetemperature of the oil bath was reduced to 50° C. and the internaltemperature was brought to 44° C. The potassium tert-butoxide (2.72 g of95% pure material) was then charged (slight exotherm to 46° C.observed). The resulting solution was then seeded with authenticCompound 1 potassium-salt ethanolate (20 mg). The temperature on the oilbath was reduced to 40° C. and the batch was aged about 1 hr. Theheating on the oil bath was turned off and the suspension was cooled to25° C. over about 1 h. The batch was then cooled in an ice bath to <5°C. and aged about 2 h. The batch was filtered through a medium porositysintered funnel and the cake dried under vacuum and nitrogen tent untila constant weight was obtained or until the amount of residual EtOHpresent by NMR (DMSO-d6) was about 80 mol % relative to Compound 1. TheCompound 1 potassium-salt (11.15) was obtained as a tightly boundethanol solvate in 78% yield (99.4 LCAP, 99.6% ee).

EXAMPLE 5N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,potassium salt ethanolate

Caprolactam HCl salt 2 (30 g≡20.4 g caprolactam HCl salt based on 68 wt% assay)) was charge to an inerted flask A with THF (240 ml) andtriethylamine (6.91 g). To flask B was charged CDI (11.53 g) and THF(110 ml). The contents of vessel A were transferred to vessel B over 50minutes and the mixture in vessel B aged for 1 h. At that point HPLCanalysis showed the formation of caprolactam acylimidazole to becomplete. Piperidine heterocycle 3 (18.2 g) was charged to vessel Bfollowed by triethylamine (15.0 g). The batch was heated to 60° C. andaged overnight when HPLC analysis showed the coupling was complete (<0.2LCAP caprolactam-CDI adduct remaining). MTBE (180 ml) and 10% aqueouscitric acid (105 ml) were added and the phases separated. The organicphase was washed again with 10% aqueous citric acid (105 ml) and thenwith 5% NaHCO₃ solution (2×100 ml). The pH of the last aqueous phase was9 at that point. The organic phase was washed with DI water (100 ml) (5ml saturated aqueous brine added to give good phase separation). HPLCassay of the MTBE solution gave an assay yield of neutral Compound 1 of31.95 g, 99.1%, 98.8 LCAP. The MTBE solution of neutral Compound 1(31.95 g) was concentrated down to low volume using partial vacuum andkeeping T<40° C. Ethanol (240 ml) was charged and the solutionconcentrated to low volume again under partial vacuum at <40° C. Ethanol(116 L) was added to bring the volume of the solution to 420 ml and thesolution assayed for neutral Compound 1: Result: 30.3 g, 53.5 mmol.Potassium tert-butoxide (6.3 g) was added and the mixture warmed to 45°C. to dissolve all the solids. The solution was then concentrated downto a final volume of 210 ml (7 ml/g based on neutral 454) at <40° C. Theresulting slurry was cooled to room temperature for 2 hours and thesolid collected by filtration. The filter cake was washed with coldethanol (100 ml) and the solid dried under vacuum at 40° C. Yield=30.2g, 87%.

EXAMPLE 6N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazol-[4,5-b]pyridin-1-yl)piperidine-1-carboxamide,Potassium Salt Ethanolate

Caprolactam HCl salt 2 (8.23 kg≡5.60 kg caprolactam HCl salt based on 68wt % assay)) was charge to an inerted vessel A with THF (66.4 L) andtriethylamine (1.90 kg). To vessel B was charged CDI (3.163 kg) and THF(30 L). The contents of vessel A were transferred to vessel B over 1.5 hand the mixture in vessel B aged for 1 h. At that point HPLC analysisshowed the formation of caprolactam acylimidazole to be complete. ThePiperidine heterocycle 3 (5.0 kg) was charged to vessel B followed bytriethylamine (4.12 kg). The batch was heated to 60° C. and agedovernight when HPLC analysis showed the coupling was complete (<0.2 LCAPcaprolactam-CDI adduct remaining). MTBE (49 l) and 10% aqueous citricacid (29 l) were added and the phases separated. The organic phase waswashed again with 10% aqueous citric acid (29 L) and then with 5% NaHCO₃solution (2×28 L). The pH of the last aqueous phase was 9 at that point.The organic phase was washed with DI water (27 L) The HPLC profileshowed still 1.0 LCAP of the caprolactam N-acylimidazole adduct impurityremaining. The MTBE solution was washed again with 10% aqueous citricacid (2×29 L), 5% aqueous NaHCO₃ (2×28 L) and water (27 L). HPLC assayof the MTBE solution gave an assay yield of neutral Compound 1 of 8.27kg, 93.5%, 98.9 LCAP, <0.1 LCAP caprolactam N-acylimidazole adduct. TheMTBE solution of neutral Compound 1 (8.27 kg) was charged to a vesselthrough a 0.1 μm cartridge filter and concentrated down to 30 L usingpartial vacuum and keeping T<40° C. Ethanol (116 L) was charged and thesolution concentrated down to 30 L again under partial vacuum at <40° C.Ethanol (116 L) was added and the solution analysed for residualTHF/MTBE (none detected). Potassium tert-butoxide (1.720 kg) was chargedas a solid to the vessel and the mixture warmed up to 45° C. to dissolveall solids. The batch was then concentrated down to a final volume of 58L (7 ml/g based on neutral 454) at <40° C. The resulting slurry was leftcooling to RT overnight before filtering. The filter cake was washedwith cold ethanol (25 L) and the solid dried under vacuum at 40° C.Yield=7.97 kg, 84%.

EXAMPLE 7

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one

Step 1: 2-Chloro-1-(2,3-difluorophenyl)ethanone

To a 5 L 4-necked round bottom flask was charged 1,2-difluorobenzene(130.0 g) and dry THF (1.3 L). This solution was cooled to <−60 whilestirring under nitrogen. To this was added n-hexyllithium (455 mL of 2.5M/hexane) dropwise such that T<−60 (˜15 minute addition). The solutionquickly turned into a stirrable slurry, which was aged for 1 hour cold.To this was added zinc chloride (2.3 L of 0.5 M/THF) such that T<−60 andthe slurry quickly became a homogeneous solution. This was warmed to 0°C. followed by the addition of copper(I) chloride (11.3 g) andchloroacetyl chloride (142 g) such that T<5° C. The reaction was assayedafter 20 minutes and judged complete by HPLC. The reaction was quenchedwith 1N HCl (2 L) and then the two phase system was transferred to aseperatory funnel and diluted with IPAc (2 L). The aqueous was cut andthe organic washed again with 1N HCl (2 L) followed by 1N NH₄OH (2×2 L)and finally with water (2 L). The organic was concentrated to an oil.Assay yield=78%. The oil is then diluted with heptane (800 mL—does notall go into solution) and stirred while cooling to −30° C. Duringcooling the oil turns over to a crystalline solid. The slurry is aged 1hour at −30° C., filtered and washed with cold heptane. Desired productisolated in 71% yield (154 g).

Step 2: 2-(2,3-difluorophenyl)-2-vinyloxirane

A solution of chloro acetophenone (40 g) in dry toluene (400 mL) wascooled to T<−60 while stirring under nitrogen. To this was added vinylmagnesium bromide (420 mL of 0.8 M in THF) dropwise such that T<−25° C.After complete addition the reaction is warmed to 0 degrees and assayedfor completion. The reaction is quenched with 1N HCl (250 mL) andtransferred to a seperatory funnel and the aqueous layer cut. Theorganic is washed again with 1N HCl (250 mL) followed by saturatedsodium bicarbonate (250 mL) and water (250 mL). The organic isconcentrated to an oil and carried forward directly.

To a solution of tertiary alcohol (210 mmol) in toluene (400 mL) isadded 1N NaOH (400 mL) and the two-phase system agitated for 4 hours atroom temperature. The organic layer is assayed by HPLC for completion.At end of reaction the aqueous layer is cut and the organic washed withwater (400 mL). The organic is concentrated/azeotropically dried invacuo and used for the next step. Typical assay yield over both steps is89%.

Step 3:N-[(3Z)-4-(2,3-difluorophenyl)-5-hydroxy-1,1-dipropionylpent-3-en-1-yl]acetamide

A 1 liter 3-necked round bottom flask equipped with a vacuum/N2 Inlet,temperature probe, addition funnel and septa was charge with Pd(OAc)₂(392 mg, 1.75 mmol, 2 mol %), DPPE (835 mg, 2.09 mmol, 2.4 mol %),N-acetodiethyl malonate (43.8 g, 201 mol, 1.15 equiv), NaOEt (1.20 g,17.5 mmol, 10 mol %), and flushed with N₂. The addition funnel wascharged with the substrate vinyl epoxide (33.6 g, 174.8 mmol) in 100 mLof toluene (KF<300 ppm). To the reaction flask was added 500 mL oftoluene (<300 ppm) and the resulting mixture flushed with N₂ and stirredat room temperature (20-25° C.) for 10 min. The vinyl epoxide solutionwas added over 5 min and the resulting mixture stirred overnight (6-10hrs) at room temperature (20-25° C.). Toluene (140 mL) and 1 N HCl (140mL) was added to the flask and the biphasic mixture transferred to aseparatory funnel. The organic layer was separated and washed with 140mL of 1 N NaOH, 140 mL of brine and 140 mL of water. The final organiclayer was treated with Darco-G60 (2-5 grams), stirred for 10 min, andfiltered. The resulting solution was concentrated (T=20-25° C.) to about300 mL volume. The solution was heated to 40-45° C. and 600 mL ofN-heptane added over 20 min. The slurry is stirred at 40-45° C. for 30min and allowed to cool to room temperature overnight. The solution wasfiltered and the solids washed with 2×120 mL of 8:1 n-heptane:toluene.The solids were dried with vacuum and N₂ sweep (70% yield).

Step 4:N-{(3Z)-4-(2,3-difluorophenyl)-1,1-dipropionyl-5-[(2,2,2-trifluoroethyl)amino]pent-3-en-1-yl}acetamide

The compound of Step 3 (50.0 g, 125.2 mmol) in 400 mL toluene (wastreated with Et₃N (16.5 g, 162.7 mmol) followed by a 25 mL toluene flushfollowed by MsCl (16.5 g, 162.7 mmol) in 120 mL toluene followed by a 25ml flush making sure the temperature did not exceed 3° C. After a 30 minage, the slurry was treated with 250 mL H₂O and then warmed to RT. Theaqueous layer was drained away (a black rag layer is observed) and theorganic phase washed with 1×200 mL 1N NaOH and 1×50 mL of 15% NaClsolution. The solution was concentrated to ˜150 mL and flushed with 300mL toluene. Addition of 375 mL of DMAC (KF ˜400) afforded the solutionready for the next step.

To the orange solution was added CF₃CH₂NH₂ (37.2 g, 376 mmol, few degreetemperature increase here) followed by LiBr (2.17 g, 26 mmol) and thesolution aged for 13 hours at 28-30° C. The reaction was diluted with250 mL IPAC and 150 mL H₂O. The aqueous layer was removed. The organiclayer was washed with 150 mL 1N NaOH and 150 mL 15% aqueous NaClsolution. Assay of the IPAC layer shows 92% yield and the solution wasconcentrated to 150 mL volume and 375 mL DMAC added.

Step 5:N-[6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-yl]acetamide

To the DMAC solution of 6 (55 g, 114.49 mmol assay, 475 mL volume) wasadded LiCl (14.5 g, 343.5 mmol) followed by H₂O (6.1 g, 343.5 mmol). Thesolution was aged at 113-115° C. for 12-14 hours (after 1 hour at 112°C. a white precipitate forms). After cooling to RT, 5 g of Darco wasadded and the solution filtered through Solka-Floc. The filter cake waswashed with 285 mL IPAC. The organic layer was split in half and cooledto 5-10° C. Each half was treated with 118.5 mL H₂O keeping thetemperature ˜15-20° C. The aqueous was back extracted with 165 mL IPACand the organic layer was washed with 220 mL 1N NaOH, 2×220 mL 15% NaClsolution brine and 220 mL of water. The solvent was switched to toluene(450 mL volume, 45 g assay).

The toluene solution (45 g, 110 mmol of decarboxylated product) wastreated with trifluoroacetic acid (143 mmol, 1.3 equiv. and a yellow oilseparated from the toluene solution. The reaction is aged at 85-90° C.for 12-15 hours overnight under nitrogen. The solution was cooled to RTand then concentrated to 3 L/kg) based on starting material and dilutedwith IPAC (338 mL). The organic layer was washed with 1N NaOH (225 mL).This resulted in an emulsion, so the batch was charged with 10 wt %celite, filtered and the cake was washed with 180 mL IPAC. The aqueousphase was cut at this point. The organic layer was washed with 1N HCl(225 mL), 225 mL 1% aqueous NaCl solution, and 5 g Darco added. Thesolution was filtered through Solka-Floc, and the solution concentratedto 4 L/kg (based on assay of product) and flushed with IPAC untilKF<100. A total of 4 volumes of heptane was added and the slurry cooledto 0° C. Filtration and washing with 0° C. 7:1 heptane:IPAC (150 mL)afforded the product as an off-white solid.

Step 6:(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium3-carboxy-2,3-bis[(4-methylbenzoyl)oxy]propanoate(di-toluoyl tartratesalt)

To a 288 mL dioxane solution of the Step 5 compound (36 g, 99.4 mmol)was added 6 equiv of 3N HCL. The solution was heated at 85° C. for 12hours. After cooling, the solution was diluted with 230 mL MTBE addedand the pH adjusted to 8-10 with 10N NaOH followed by 1N NaOH. After thephase cut, the aqueous was extracted with 230 mL MTBE and the combinedorganic layer washed with 390 mL 15% NaCl and assayed for product (25.4g, 79.3 mmol, 80% assay yield). The solution was concentrated to ˜10L/kg of amine and then solvent switched to IPA (˜762 mL total volume).The KF of the solution was adjusted to 4000 ppm and then2-hydroxy-5-nitrobenzaldehyde (7.9 mmol) was added followed by(−)—O,O′-di-toluoyl-L-tartaric acid (158.6 mmol) and the resultingslurry was aged at 65° C. for 130 hours. The slurry was then filteredand the solid washed with IPA.

Step 7:(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumChloride

The compound of step 6 (10 g, 14.15 mmol) di-toluoyl tartrate salt wasslurried in i-PrOH (93 mL). To this mixture was added 1N HCl (15.57 mL,1.10 equiv) and the mixture became homogeneous. After sparging withnitrogen, 5% Pd/BaSO₄ (1.20 g, 4 mol %) was added and hydrogenated at 80psi of hydrogen for 20 h, or until all consumed by HPLC. The solutionwas filtered through Solka Floc with MeOH (50 mL) to remove catalyst.The filtrate was concentrated to 2 mL/g and then diluted with MTBE (100mL) and then 1N NaOH (80 mL). After the phase cut, the aqueous was backextracted with 70 mL of MTBE. The organic solution was washed with brine(70 mL) (HPLC assay for yield of cis form) and solvent switched to MeOHuntil <5% MTBE and KF ˜1500 ppm with a total volume of 45 mL and thentreated with Et₃N (3.95 mL, 2 equiv. relative to cis form) and2-hydroxy-5-nitrobenzaldehyde (237 mg, 10 mol % relative to cis form).The solution was stirred at room temperature for 20 hours which resultsin ˜20:1 ratio of trans:cis forms of the title compound. The solutionwas diluted with MTBE (100 mL) and then 1N NaOH (80 mL) added. After thephase cut, the aqueous was back extracted with 70 mL of MTBE. Thecombined organics were then washed with 70 mL of brine, conc. to 25%volume and filtered. The organic solution was concentrated further andthen MTBE was added until volume was 30 mL. To this was then added 15 mLof MeOH (KF ˜1500 ppm). After heating solution to 50° C., 1% seed of thetitle compound was added followed by a 2 hour addition of 5N HCl in IPA(5.6 mL, 2.2 equiv. relative to cis form assay). This was then aged 1hour at 50° C. and then cooled to room temperature over 3 hours. Afteraging overnight at RT, the slurry was filtered and washed with 3:1MTBE:MeOH (2×15 mL). The cake was then dried 20 h under vacuum at roomtemperature to give the title compound as an HCl salt.MTBE solvate in85% yield (5.37 g, 99% ee).

EXAMPLE 8 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridineStep 1: Ethyl 4-[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate

To a 1 L three-neck RB-flask equipped with a mechanical agitator andtemperature probe was charged 3-amino-2-chloropyridine (37.9 g, 0.294mol, 100 mol %) and ethyl 4-oxo-1-piperidinecarboxylate (55.5 g, 0.324mol, 110 mol %) followed by IPAC (500 mL). The mixture becamehomogeneous after 5 min agitation (16° C.). Trifluoroacetic acid (44 mL,0.590 mol, 200 mol %) was charged to the mixture over 30 s, causing anincrease in temperature to 25° C. (no cooling used). Sodiumtriacetoxyborohydride (75.0 g, 0.354 mol, 120 mol %) was added as asolid over 5 min and a further increase in temperature to 56° C. wasobserved. After 10 min agitation, the mixture was clear and homogeneous.LC analysis indicated consumption (<0.5 A %) of 3-amino-2-chloropyridineand formation of the alkylated product. A solution of 10 wt % aqueousNaOH was added to the mixture at 50° C. over 10 min. When the pH of themixture was 8-9, the phases were allowed to separate. The organic phasewashed with brine (200 mL). The separated aqueous phase was 580 mL—100μL sample was diluted in 100 mL MeOH and LC analysis indicated 0.23 g,0.3% of product was present. The brine was assayed as above andcontained negligible product. Azeotropic drying with IPAC was conductedat atmospheric pressure under constant volume conditions until the watercontent was <500 ppm by KF titration. The solution was concentrated to avolume of 170 mL then THF (35 ppm H₂O, 230 mL) was added. This solutionwas used directly for the subsequent step. LC analysis gave 84 g, 101%AY of the desired reductively alkylated product and KF titration gavewater content as <500 ppm.

Step 1 (Alternate): Ethyl4-[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate

To a 2 L three-neck Morton-type flask equipped with a mechanicalagitator and temperature probe was charged 3-amino-2-chloropyridine andethyl 4-oxo-1-piperidinecarboxylate followed by IPAC. The mixture becamehomogeneous after 5 min agitation (16° C.). Trifluoroacetic acid wascharged to the mixture over 30 s, causing an increase in temperature to26° C. (no cooling used). After 15 min age, a caplet of NaBH₄ (0.95 g,0.025 mol) was added. The temperature was observed to increase to 28° C.over a 30 min period and the caplet dissolved completely within thistime. This method of NaBH₄ addition was repeated, allowing each capletto dissolve before adding the next, until a total of eight caplets hadbeen added over 7 h. At this time, LC analysis indicated >95% conversionof the 3-amino-2-chloropyridine. A solution of 10 wt % aqueous NaOH wasadded to the mixture at 30-40° C. (no cooling) over 10 min. When the pHof the mixture was 12-14, the phases were allowed to separate. Theseparated aqueous phase was 450 mL and LC assay indicated this contained0.5 g, <1.0% of product. The organic phase washed with brine then theseparated organic phase was assayed. The separated brine wash was 275 mLand LC assay indicated this contained negligible product. The organicphase was 690 mL and LC assay indicated this contained 87.5 g, 97% AY ofreductively alkylated product and 2.1 g, 5% of starting amine. Theyellow organic phase was concentrated (45° C. bath temperature) toapproximately one-third original volume. Fresh IPAC was added and thisprocess was repeated until the water content was 110 μg/mL by KFtitration. The solution was concentrated to a volume of 170 mL then THF(230 mL) was added. This solution was used directly for the subsequentstep.

Step 2: Ethyl4-[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate

To a 1 L three-neck RB-flask equipped with a mechanical agitator andtemperature probe was charged with THF (250 mL, KF 35 ppm H₂O) thenchlorosulfonyl isocyanate (CSI) (30.7 mL, 0.353 mol, 120 mol %) wasadded at room temperature (negligible exotherm). The mixture was cooledto −10° C. using ice/MeOH. The solution of amine prepared above in Step1 (83.42 g, 0.294 mol, 100 mol %) in THF: IPAC (˜1:1) (400 mL, KF ofthis solution was 500 ppm) was added over a 20 min period via a droppingfunnel. An exotherm was observed during this addition (max. temp. 2°C.). Upon completion of the amine solution addition LC analysisindicated consumption of the amine (<1.0 A %)—sample was prepared bydilution in 0.1% H₃PO₄/MeCN (70:30) and rapid injection on the LCinstrument indicated one major component. After 10 min, water (30 mL)was added dropwise over a 10 min period. A second exotherm was observedduring the water addition (max. temp. 17° C.). The mixture was allowedto warm to rt and aged for 14 h. The pH at EOR was approximately 1. Thehydrolysis was complete (<0.5 A % intermediate) within 30 min of thewater addition as monitored by LC analysis. The mixture was treated with10% aq. NaOH until pH 8-9 and the separated organic phase was washedwith brine (300 mL). The work-up was conducted at 50° C. to maintainsolubility of the product. The separated aqueous volume was 500 mL—100μL sample was diluted in 100 mL of above sample diluent and LC analysisindicated 1.38 g, 1.4% of product was present. The brine was assayed asabove and contained negligible product. Azeotropic drying with IPAC wasconducted at atmospheric pressure under constant volume conditions untilthe water content was <250 ppm by KF titration. The urea crystallizedand the slurry was concentrated to ˜5 volumes then allowed reach rtbefore the product urea was collected by filtration. The cake was rinsedwith 2 bed volumes IPAC. After drying for 12 h at 50-60° C. undervacuum, the product urea was obtained as a white solid (81.41 g, 85%isolated yield, 96 wt %).

Step 3: Ethyl4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

To a 500 mL three-neck Morton-type flask equipped with a mechanicalagitator, reflux condenser and temperature probe was charged NaHCO₃(25.21 g, 0.300 mol, 300 mol %), urea of Step 2, above (32.69 g, 0.100mol, 100 mol %), and i-PrOH (KF 1415 ppm, 320 mL). The heterogeneousmixture was agitated and purged with N₂ using an M-fritted gasdispersion tube. After 1 h, the Pd(OAc)₂ (0.224 g, 0.001 mol, 1 mol %)and bis-(diphenylphosphino)butane (dppb) 0.854 g, 0.002 mot, 2 mol %)were added as solids and the N₂ purge continued for a further 30 min.The pink mixture was then heated to 83° C. (reflux) for 24 h. After thistime, LC analysis of the yellow mixture indicated >99.5:0.5 A % ratio ofproduct to starting material. Atmospheric pressure distillation of thei-PrOH was initiated and continued until 200 mL i-PrOH distillate hadbeen collected. IPAC (200 mL) and water (100 mL) were added and thetemperature was maintained at 60° C. After 30 min agitation, the phaseswere allowed to separate. The organic phase was clear yellow and theaqueous was colorless. The separated aqueous volume was 75 mL—100 μLsample was diluted in 100 mL of MeOH and LC analysis indicated 0.03 g,0.1% of product was present. The organic phase was washed with brine(3×75 mL). Azeotropic drying with IPAC was conducted at atmosphericpressure under constant volume conditions until the water content was<150 ppm measured by KF titration. The product crystallized to produce aslurry at 90° C. The slurry was concentrated to ˜5 volumes and allowedto cool to rt before it was filtered and the cake was washed with 2 bedvolumes IPAC. The solid was dried in a vacuum oven @ 50-60° C. under annitrogen sweep for 16 h. A cyclic urea was obtained as a white solid(27.4 g, 94% isolated, 96 wt %).

Step 4: 1-piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneDihydrochloride

To a 100 mL three-neck RB-flask equipped with a mechanical agitator,reflux condenser and temperature probe was charged the cyclic urea madein Step 3, above (4.80 g, 16.48 mmol, 100 mol %) followed by EtOH (10mL). To the resultant slurry was added aqueous NaOH (13 mL of 50 wt %solution diluted with 12 mL water, 246.0 mmol, 1500 mol %) and themixture was heated to 82° C. (reflux) for 14 h. LC analysis indicatedconsumption (<0.5 A %) of the cyclic urea and formation of the amineproduct 3—sample was prepared by dilution in 0.1% H₃PO₄/MeCN (70:30).Water (25 mL) and i-BuOH (25 mL) were added and the mixture was agitatedfor 10 min then the phases were allowed to separate. The separatedaqueous volume was 41 mL—100 μL sample was diluted in 100 mL of abovediluent and LC analysis indicated 0.26 g, 5% of product was present. Theseparated aqueous volume was 54 mL—100 μL sample was diluted in 100 mLof above diluent and LC analysis indicated 4.13 g, 86% of product waspresent. Azeotropic drying with i-PrOH was conducted at atmosphericpressure under constant volume conditions until the water content was150 ppm measured by KF titration. The volume was adjusted to 100 mL andthe temperature allowed to reach 50° C. HCl in i-PrOH (5-6 N, 20 mL,0.100 mol, 600 mol %) was added, causing an immediate white precipitate.After cooling to rt, the slurry was filtered and the cake was rinsedwith 2 bed volumes i-PrOH. The white solid was dried in a vacuum oven @50-60° C. under a nitrogen sweep for 24 h. The title pyridineheterocycle bis-HCl salt was obtained as a white solid (5.54 g @ 78 wt %giving 89% isolated yield, with the residual wt % consisting of NaCl).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A process for the preparation of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,said process comprising the steps of: (1) hydrogenating a(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumsalt, in the presence of a cis-selective catalyst, to form a(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt; and (2) reacting the(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt with R₃N, wherein each R is independently C₁₋₄ alkyl, and ahydroxyl nitrobenzaldehyde.
 2. A process for the preparation of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, said process comprising the steps of: (1) hydrogenating a(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumsalt, in the presence of a cis-selective catalyst, to form a(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt; (2) reacting the(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt with R₃N, wherein each R is independently C₁₋₄ alkyl C₁₋₄alkyl, anda hydroxyl nitrobenzaldehyde, to form(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;and (3) reacting(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onewith HCl.
 3. (canceled)
 4. (canceled)
 5. A process for the preparationof the intermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one,comprising the steps of: (1) reacting3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-onewith 2-hydroxy-5-nitrobenzaldehyde and a chiral acid to form an(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumsalt; (2) hydrogenating a(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumsalt, in the presence of a cis-selective catalyst, to form a(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt; and, (3) reacting the(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumsalt with R₃N, wherein each R is independently C₁₋₄ alkyl, and ahydroxyl nitrobenzaldehyde, to form(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.6. (canceled)
 7. (canceled)
 8. A process for the preparation of theintermediate(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride, comprising the steps of: (1) reacting3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-onewith 2-hydroxy-5-nitrobenzaldehyde and ditoluoyl-L-tartaric acid to forman(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumsalt; (2) hydrogenating(3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammoniumdi-toluoyl tartrate salt, in the presence of a cis-selective palladiumcatalyst, to form(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumdi-toluoyl tartrate salt; (3) reacting(3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammoniumdi-toluoyl tartrate salt with Et₃N and 2-hydroxy-5-nitrobenzaldehyde toform(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one;and (4) reacting(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onewith HCl.
 9. The process of claim 1, wherein the ammonium salt of claim1, steps (1) and (2) is a di-toluoyl tartrate salt.
 10. The process ofclaim 1, wherein the cis-selective catalyst of claim 1, step (1) is acis-selective palladium catalyst.
 11. The process of claim 1, whereineach R group of step (2) is ethyl.
 12. The process of claim 2, whereinthe ammonium salt of claim 1, steps (1) and (2) is a di-toluoyl tartratesalt.
 13. The process of claim 2, wherein the cis-selective catalyst ofclaim 1, step (1) is a palladium catalyst.
 14. The process of claim 2,wherein each R group of step (2) is ethyl.
 15. The process of claim 5,wherein the chiral acid of step (I) is di-toluoyl-L-tartaria acid andthe ammonium salt of steps (1) and (2) is a di-toluoyl tartrate salt.16. The process of claim 5, wherein the cis-selective catalyst of claim1, step (1) is a cis-selective palladium catalyst.
 17. The process ofclaim 5, wherein each R group of step (3) is ethyl.
 18. The process ofclaim 5, further comprising the step of (4) reacting(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onewith HCl to form(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-onehydrochloride.